MRTX1133
目录号 : GC62699
MRTX1133 是一种非共价、有效和选择性的 KRAS G12D 抑制剂。 MRTX1133 以最佳方式填充开关 II 口袋并延伸三个取代基以有利地与蛋白质相互作用，导致对 KRAS G12D 的估计 KD 为 0.2 pM。 MRTX1133 阻止 SOS1 催化的核苷酸交换和/或 KRAS G12D/GTP/RAF1 复合物的形成，从而抑制突变的 KRAS 依赖性信号转导。 MRTX1133 选择性抑制 KRAS G12D 突变体，但不抑制 KRAS 野生型肿瘤细胞。 MRTX1133 在细胞试验中具有个位数的纳摩尔活性，并且在含有 KRAS G12D 突变的肿瘤模型中具有显着的体内功效。
Cas No.:2621928-55-8
Sample solution is provided at 25 µL, 10mM.
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MRTX1133 is an exceptionally potent and selective KRASG12D inhibitor with high affinity (<2nM).[1]
In vitro, in the AGS cell line, MRTX1133 inhibited ERK phosphorylation with an IC50 of 2 nM. In the meanwhile, MRTX1133 was against the same cell line with an IC50 of 6 nM in a 2D viability assay.[1] In vitro efficacy test, in KRASG12D–mutant HPAC Cells, it indicated that treatment with 0.05 nM - 300 nM MRTX1133 has a dose-dependent pERK, pS6 & DUSP6 modulation.[2]
In vivo experiment it shown that treatment with 30 mg/kg of MRTX1133 intraperitoneally in CD-1 mice caused the sustained plasma exposure exceeding the free-fraction-adjusted pERK IC50 value in the KRASG12D mutant Panc 04.03 cell line for approximately 8 h. And in the Panc 04.03 xenograft tumor model, it suggested that MRTX1133 (3-30 mg/kg, i.p.) has dose-dependent antitumor activity with 94% growth inhibition observed at 3 mg/kg BID (IP) and tumor regressions of ?62% and ?73% observed at 10 and 30 mg/kg BID (IP), respectively.[1]
References:
[1].Wang X, Allen S, et al. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D?Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133.
[2].Swiatnicki M, Engel L, Shrestha R, Alves J, Goueli SA, Zegzouti H. Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay. SLAS Discov. 2022 Jun;27(4):249-257.?
MRTX1133 是一种非常有效的选择性 KRASG12D 抑制剂，具有高亲和力 (<2nM)。[1]
在体外，在 AGS 细胞系中，MRTX1133 抑制 ERK 磷酸化，IC50 为 2 nM。同时，MRTX1133 在 2D 活力测定中针对同一细胞系，IC50 为 6 nM。[1] 体外药效测试，在 KRASG12D-突变体中HPAC 细胞，它表明用 0.05 nM - 300 nM MRTX1133 处理具有剂量依赖性 pERK，pS6 &； DUSP6 调制。[2]
体内实验表明，在 CD-1 小鼠中用 30 mg/kg 的 MRTX1133 进行腹膜内处理会导致持续的血浆暴露超过 KRASG12D 突变体中自由分数调整的 pERK IC50 值Panc 04.03 细胞系约 8 小时。在 Panc 04.03 异种移植肿瘤模型中，它表明 MRTX1133（3-30 mg/kg，i.p.）具有剂量依赖性抗肿瘤活性，在 3 mg/kg BID (IP) 时观察到 94% 的生长抑制和 -62 的肿瘤消退% 和 -73% 分别在 10 和 30 mg/kg BID (IP) 下观察到。[1]
| Cas No. | 2621928-55-8 | SDF | |
| 分子式 | C33H31F3N6O2 | 分子量 | 600.63 |
| 溶解度 | 储存条件 | Store at -20°C | |
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Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor
J Med Chem 2022 Feb 24;65(4):3123-3133.PMID:34889605DOI:10.1021/acs.jmedchem.1c01688.
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Nat Med 2022 Oct;28(10):2171-2182.PMID:36216931DOI:10.1038/s41591-022-02007-7.
Recent progress in targeting KRASG12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRASG12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRASG12D with KD and IC50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRASG12D as compared to KRASWT. MRTX1133 also demonstrated potent inhibition of activated KRASG12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRASG12D-mutant cell lines, with median IC50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRASWT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRASG12D-mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRASG12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRASG12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival.
Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer
Cancer Discov 2023 Feb 6;13(2):298-311.PMID:36472553DOI:10.1158/2159-8290.CD-22-1066.
Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. Significance: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247.
Characterization of the binding of MRTX1133 as an avenue for the discovery of potential KRASG12D inhibitors for cancer therapy
Sci Rep 2022 Oct 22;12(1):17796.PMID:36273239DOI:10.1038/s41598-022-22668-1.
The Kirsten rat sarcoma (KRAS) oncoprotein has been on drug hunters list for decades now. Initially considered undruggable, recent advances have successfully broken the jinx through covalent inhibition that exploits the mutated cys12 in the switch II binding pocket (KRASG12C). Though this approach has achieved some level of success, patients with mutations other than cys12 are still uncatered for. KRASG12D is the most frequent KRAS mutated oncoprotein. It is only until recently, MRTX1133 has been discovered as a potential inhibitor of KRASG12D. This study seeks to unravel the structural binding mechanism of MRTX1133 as well as identify potential drug leads of KRASG12D based on structural binding characteristics of MRTX1133. It was revealed that MRTX1133 binding stabilizes the binding site by increasing the hydrophobicity which resultantly induced positive correlated movements of switches I and II which could disrupt their interaction with effector and regulatory proteins. Furthermore, MRTX1133 interacted with critical residues; Asp69 (- 4.54 kcal/mol), His95 (- 3.65 kcal/mol), Met72 (- 2.27 kcal/mol), Thr58 (- 2.23 kcal/mol), Gln99 (- 2.03 kcal/mol), Arg68 (- 1.67 kcal/mol), Tyr96 (- 1.59 kcal/mol), Tyr64 (- 1.34 kcal/mol), Gly60 (- 1.25 kcal/mol), Asp12 (- 1.04 kcal/mol), and Val9 (- 1.03 kcal/mol) that contributed significantly to the total free binding energy of - 73.23 kcal/mol. Pharmacophore-based virtual screening based on the structural binding mechanisms of MRTX1133 identified ZINC78453217, ZINC70875226 and ZINC64890902 as potential KRASG12D inhibitors. Further, structural optimisations and biochemical testing of these compounds would assist in the discovery of effective KRASG12D inhibitors.
KRAS inhibitors: going noncovalent
Mol Oncol 2022 Dec;16(22):3911-3915.PMID:36383067DOI:10.1002/1878-0261.13341.
KRASG12D is the most frequent KRAS mutation in human cancer with particularly high frequencies in pancreatic and colorectal cancer. Informed by the structure of the KRASG12C inhibitor adagrasib, Hallin et al. have now, through multiple rounds of structure-based drug design, identified and validated a potent, selective, and noncovalent KRASG12D inhibitor, MRTX1133. This study demonstrated that MRTX1133 inhibited both the inactive and active state of KRASG12D and showed potent antitumor activity in several preclinical models of pancreatic and colorectal cancer, especially when combined with cetuximab, a monoclonal antibody against the EGFR, or BYL-719, a potent PI3Kα inhibitor.